Substituted pyrazolopyrimidines are known as actives for anxiolytic, anticonvulsant, antiepileptic, sedative-hypnotic and skeletal muscle relaxant agents. Illustrative substituted pyrazolopyrimidines include N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide, (hereinafter zaleplon, discussed below), and N-methyl-N-(3-{3-[2-thienylcarbonyl]pyrazolo[1,5-a]-pyrimidin-7-yl}phenyl)acetamide (herein after Indiplon™, disclosed in U.S. Pat. No. 6,399,621).
Zaleplon is known as having anxiolytic, antiepileptic, sedative and hypnotic properties. The U.S. F.D.A. has approved zaleplon for use for short-term treatment of insomnia. The prior art discloses a method for preparing zaleplon in U.S. Pat. No. 4,626,538, wherein N-(3-acetylphenyl)ethanamide is condensed with dimethylformamide dimethyl acetal to form N-[3-[3-(dimethylamine)-1-oxo-2-propenyl)]phenyl]acetamide. The primary amide of the acetamide is then alkylated with ethyl iodide to form N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide. The ethylacetamide is then condensed with 3-amino-4-cyanopyrazole in refluxing glacial acetic acid for eight hours until the conversion to zaleplon is substantially complete.
U.S. Pat. No. 5,714,607 discloses an improvement over the '538 process for producing zaleplon. It is claimed in the '607 patent that improved yield and purity can be obtained at a faster rate if the final step of the '538 process is modified by adding water to the acetic acid solvent at about 10% to about 85% (v/v). The improved conditions are stated to shorten the reaction time from 3-3.5 to 1-3.5 hours. The improved reaction is said to result in yields ranging from 81.7-90% with purity ranging from 98.77 to 99.4% according to HPLC analysis.
WO O2/100828 A2 discloses a further improvement in the '538 process by reacting the same intermediates, N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide and 3-amino-4-cyanopyrazole, in a liquid medium of water and a water-miscible organic compound under acidic conditions. Although the reaction is claimed to proceed through an imine intermediate that was prone to precipitate from water, the imine intermediate remained dissolved in the reaction media. It is stated in the '828 patent that the process proceeds rapidly at ambient temperature to produce zaleplon with a 91-97% yield having a purity ranging from 98.7 to 99.5% according the HPLC analysis. The method minimized the formation of a regioisomer by-product, N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-N-ethylacetamide which is favored under excess acid conditions.
It is therefore desirable to have an improved process for the preparation of substituted pyrazolopyrimidines that results in near quantitative conversion after a few hours at ambient temperature.